Novel 3,5-substituted 2,4,6-triiodobenzoic acids and salts thereof

ABSTRACT

WHEREIN R1 is methyl or ethyl and R2 and R3 are each acetyl or propionyl and wherein A is an alkylene group substituted by at least one hydroxy group, said alkylene containing from three to 15 carbon atoms and being optionally broken by one or more oxygen bridges; or physiologically acceptable salts of said compounds.   Iodo compounds useful in the X-ray visualization of body cavities, of the formula:

United States Patent Bjork et al.

[ NOVEL 3,5-SUBSTITUTED 2,4,6-

TRIIODOBENZOIC ACIDS AND SALTS THEREOF [72] Inventors: Lars Bjork, Uno E. Erikson,

Bjorn G.-A. Ingelman, all of Upsala, Sweden '[73] Assignee: Pharmacia Aktiebolog, Uppsala,

Sweden [22] Filed: April 10, 1970 211 Appl. No.: 27,437

Related US. Application Data [63] Continuation-in-part of Ser. No. 689,724, Dec.

ll, 1967, abandoned.

[30] Foreign Application Priority Data Dec. 13, 1966 Sweden ..l-7053/l966 [52] US. Cl. ..260/501.11, 260/519, 424/5 [51] Int. Cl. ..C07c 103/32 [58] Field of Search ..260/50l.l 1, 519

[56] References Cited UNITED STATES PATENTS Ackerman ..260/519 51 Sept. 19, 1972 Primary Examiner-Lorraine A. Weinberger Assistant Examiner-L. Arnold Thaxton Attomey-Fred C. Philpitt [57] ABSTRACT iodo compounds useful in the X-ray visualization of body cavities, of the formula:

12 Claims, No Drawings tures, for example, in range of C to 50C such as C, 30C and 40C.

EXAMPLE 1 0.1 mole of 3-acetylamino-5-acetyl-methylamino- 2,4,6-triiodobenzoic acid was dissolved in 50 ml of an aqueous 4 N solution of sodium hydroxide. 0.05 mole of bis[2,3-epoxypropyl1ether was slowly added dropwise to the solution at 40C under agitation for 4 hours. The reaction mixture was then allowed to stand for 24 hours at 20C, whereupon an aqueous 6 N solution of hydrogen chloride was added in an amount sufficient to precipitate the dicarboxylic acid formed during the reaction. The acid was cleansed by washing it with water and repeated precipitations, and the acid finally dried under vacuum at 50C. The yield of the dicarboxylic acid was about 60 grams.

Solutions may be prepared from the obtained acid by adding water and, e.g., equivalent amounts of sodium hydroxide or methyl glucamine.

EXAMPLE 2 0.1 mole of 3-acetylamino-5-acetylmethylamino- 2,4,6-triiodobenzoic acid was dissolved in 50 ml of an aqueous 4 N solution of sodium hydroxide. 0.05 mole of l,2-ethanedioldiglycide ether was slowly added to the solution dropwise at 40C under agitation for 4 hours. The reaction mixture was then allowed to stand for 24 hours at 20C, whereupon an aqueous 6 N solution of hydrogen chloride was added in an amount sufficient to precipitate the dicarboxylic acid formed in the reaction. The acid was cleansed by washing with water and repeated precipitations were effected and said acid dried under vacuum at 50C. The yield of dicarboxylic acid was about 60 grams.

Solutions can be prepared from the obtained acid by adding water and, e.g., equivalent amounts of sodium hydroxide or methyl glucamine.

EXAMPLE 3 0.1 mole of 3-acetylamino-5-acetyl-methylamino- 2 ,4,6-triiodobenzoic acid was dissolved in 50 ml of an aqueous 4 N solution of sodium hydroxide. 0.05 mole of 1,4-butanedioldiglycide ether was slowly added to the mixture dropwise at 40C under agitation for 4 hours. The reaction mixture was then allowed to stand for 24 hours at 20C, whereupon an aqueous 6 N solution of hydrogen chloride was added in an amount sufficient to precipitate the dicarboxylic acid formed in the reaction. The acid was cleansed by washing and repeated precipitations, and said acid dried under vacuum at 50C. The yield of dicarboxylic acid was about 60 grams.

The obtained acid can be transferred into salts, from which aqueous solutions can be prepared as in Example 1 and Example 2.

EXAMPLE 4 In a similar manner to that of example I, 0.1 mole of 3-acetylamino-S-acetyl-methylamino-Z,4,6- triiodobenzoic acid was reacted with 0.05 mole of epichlorohydrin or with 0.05 mole of epibromohydrin or with 0.05 mole of dichlorohydrin.

Cleansing of the dicarboxylic acid formed in the reaction carried out in a manner similar to that of Example 1.

EXAMPLE 5 Solutions were prepared from each of the dicarboxylic acids obtained in examples 1,2, 3 and 4, in the following manner.

35 grams of substance and equivalent amounts of methyl glucamine were dissolved in water to a solution volume of ml. pH was adjusted to 7.3 7.4. The solution was filtered and poured into bottles, which were sealed and sterilized in an autoclave.

EXAMPLE 6 The solutions from Example 5 were injected in the blood vessels of rabbits, whereupon the blood vessels were made visible by X-rays and photographs.

After a while, e.g. after 30 minutes, i hour and 2 hours, X-ray exposure and photographing of the gas troarea showed a good contrast filling of the gall bladder and bile ducts.

EXAMPLE 7 Solutions from example 5 were administered orally to rabbits whereafter the gastro-intestinal tract were made visible by X-rays and photographs, with excellent results.

EXAMPLE 8 Solutions of sodium salt of the compounds prepared in a manner similar to that of example 5 containing 20 grams of dicarboxylic acids per 100 ml solution were administered in the form of an enema to rabbits, whereupon the intestines could be observed by X-rays and photographs; with good results.

EXAMPLE 9 0.1 mole of 3-acetylamino-5-acetyl-methylamino- 2,4,6-triiodobenzoic acid was dissolved in 50 ml of an aqueous 4N solution of sodiumhydroxide. 0.05 mole of 1,3-butanedioldiglycide ether was slowly added to the mixture dropwise at 30C while stirring for 6 hours.

The reaction mixture was then left at 20C for 48 hours, whereupon an aqueous 6N solution of hydrogen chloride was added in an amount sufficient to precipitate the dicarboxylic acid formed in the reaction. The acid was cleansed by washing and repeated precipitations, and said acid dried under vacuum at 50C. The yield of dicarboxylic acid was about 60 grams.

EXAMPLE In the same manner as that of example 9, 0.1 mole of 3-acety1amino-5-acetyl-methy1amino-2,4,6- triiodobenzoic acid was reacted with 0.05 mole of 1:2, 3:4-diepoxybutane The cleansing of the dicarboxylic acid formed in the reaction was carried out in the same manner as that of example 9. A solution was prepared and tested in rabbits in the same manner as that of example 9.

EXAMPLE 1 1 In the same manner as that of example 9, 0.1 mole of 3-acetylamino-5-acetyl-methylamino-2,4,6- triiodobenzoic acid was reacted with 0.05 mole of 1,3- glyceroldiglycide ether EXAMPLE l2 7 0.1 mole of 3-acety1amino-5-acetyl-ethylamino-2,4,6 -triiodobenzoic acid was dissolved in 90 ml of an aqueous 2N solution of sodium hydroxide. 0.05 mole of 1,4- butanedioldiglycide ether was slowly added to the mixture dropwise at 30C while stirring for 6 hours. The reaction mixture was then left at 20C for 2 days, whereupon the dicarboxylic acid formed in the reaction was precipitated wi h HCl and cleansed in the same way as in example 9. A solution of the methyl glucamine salt was prepared and tested in rabbits in the same manner as in example 9, with good results.

EXAMPLE 13 In a similar manner to that of example 12, 0.1 mole of 3-acetylamino-5-acetyl-ethy1amino-2,4,6- triiodobenzoic acid was reacted with 0.05 mole of 1:2, 3:4-diepoxybutane the dicarboxylic acid formed in the reaction was cleansed and tested in rabbits in a similar manner to that of example 12.

EXAMPLE l4 1 mole of 3-acetylamino-5-acetyl-methylamino-2,4,6 -triiodobenzoic acid was dissolved in 560 ml of an aqueous 2.2N solution of sodium hydroxide. 0.45 mole of 1,4-butanedioldig1ycide ether was slowlyadded to the mixture dropwise for 8 hours at 25C with continuous stirring. The reaction mixture was then left at 20C for 64 hours, whereupon it was diluted with twice its volume of water and an aqueous 5N solution of hydrogen chloride was added in an amount suflicient to precipitate the dicarboxylic acid formed in the reaction.

The acid. was cleansed by washing with water, and the product was dried under vacuum at 60C.

In this example about 10 per cent excess of 3- acetylamino-S-acetyl-methylamino-2,4,6-triiodobenzoic acid was used. In order to get rid of the excess of the monocarboxylic acid in the crude dicarboxylic acid product, the crude dried product was suspended in 800 ml methanol. (The dicarboxylic acid is soluble in methanol. The monocarboxylic acid has a very low solubility in in methanol). The methanol solution was separated from substance which had not been dissolved. The methanol solution containing the dicarboxylic acid was evaporated to dryness. The product was dissolved in l 1 IN aqueous NaOH solution, whereupon an aqueous 5N solution of HCl was added in an amount sufiicient to precipitate the dicarboxylic acid.

The dicarboxylic acid was dissolved and reprecipitated once more in the-same manner. The product was well washed with water, whereupon it was dried under vacuum at 60C.

450 grams of the purified dicarboxylic acid and equivalent amounts of methylglucamine were dissolved in water to a solution volume of 1,000 ml. pH was adjusted to 7.3 7.4. The solution was filtered and poured into bottles which were sealed and sterilized in an autoclave at l 10C for 35 minutes. The solution was used in angiography with excellent results.

What we claim is:

1. A compound selected from the group consisting of (A) compounds of the formula R2 a a R2 Bri l-c o-lvflt-ir-c o-r I-In .i 4... 1.4 door; boon wherein R is a member selected from the group consisting of methyl and ethyl and R and R; are each a member selected from the group consisting of acetyl and propionyl and wherein A is an alkylene group substituted by at least one substituent of the fonnula OH; said alkylene containing from three to 15 inclusive carbon atoms, and (B) physiologically acceptable salts thereof.

2. A compound as claimed in claim 1, wherein the bridge has each nitrogen atom thereof located at a distance of two carbon atoms from a group OH and no more than one oxygen atom is bound to one and the same carbon atom in the bridge A.

3. A compound as claimed in claim 1, wherein the bridge A of the compound is a member selected from the group consisting of CH,.CH(OH).CH, 1 and CH,.CH(OH).CH(OH).CH,

4. A compound selected from the group consisting of (A) compounds of the formula CH3 I CH: CH; I CH: o co be o co omit-c ca l-Fi m 04 1 011, I-(J 0.1 1-0 0-1 wherein A is an alkylene group substituted by at least one substituted of the formula -OH; said alkylene containing from three to 15 inclusive carbon atoms, and (B) physiologically acceptable salts thereof.

5. A compound of the formula and non-toxic salts thereof.

7. A compound selected from the group consisting of (A) compounds of the formula wherein R is a member selected from the group consisting of methyl and ethyl and R, and R, are each a member selected from the group consisting of acetyl and propionyl and wherein A is an alkylene group substltuted by at least one substituent of the formula OH; said alkylene containing from three to inclusive carbon atoms and being broken by at least one oxygen bridge of the salts 0 and (B) physiologically acceptable salts thereof. A

8. A compound as claimed in claim 7, wherein the bridge has each nitrogen atom located at a distance of two carbon atoms from a group OH and that no more than one oxygen atom is bound to one and the same carbon atom in the bridge A.

9. A compound as claimed in claim 7, wherein the bridge A is a member selected from the group consisting of CH,.CH(OH).CH,.O.(CH,) .O.CH,.CH(Ol-l).CI-l,

- -and CH3 cH,-or1 0H -cm-O-oH-cm-cm-o-omomom-omi V. CH,.CH(OH).CH .O.CH .CH,.0.CH,.CH,.0.CH ,.CH(OH).CH,

10. A compound selected from the group consisting of (A) compounds of the formula on, I on, on. I on. :0 o co co 5 c0 omit-o c-r z-re-no c-n-om Li 0-1 1- 1 0 i 01: NW coon wherein A is an alkylene group substituted by at least one substituent of the formula -OH; said alkylene containing from three to 15 inclusive carbon atoms and being broken by at least one oxygen bridge of the formula O and (B) physiologically acceptable salts thereof.

11. A compound of the formula on; I OH; on, I OH; co 5 (30 oo o oo CHg-N-C C-N-A-N-O C-N-CHa C F boon 00011 wherein A 15 a member selected from the group consisting of 11 l g CH1 on, I on, on, I cm CHz-CH(OH)'CHQ-O-CH-CHZ-CHTO-CH2OH(OH)-CHz oo o 00 o oo and V omN-o C-NAN-C (LN-CH:

1-0 0.1 1.0 0-1 -CH .CI-I(OH).CH .O.(CH .O.CH,.CH(OH).CH, 5 f C and l 0 OH 0 0 0H -CH .CH(0H).CH,.O.CH,.CH(OH).CH, and wherein A is (J CH,.CH(OH).CH,.O.CH,.CH(OH).CH,.O.CH 0H).CH, O (CH,) .O.CH,.CH(OH).CH, ,.CH(OH).CH and non-toxic salts thereof. and nomtoxic salts thereof 12. A compound of the formula ny n:

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No. 3, 92, 24 Dated September 19, 1972 Inventor(s)LARS BJORK; UNO E ERIKSON; BJORN G.A INGELMAN It is certified that error appears in the above-ideutified patent and that said Letters Patent are hereby corrected as shown below! In column 10, line 8 should read "bridge of the formula O and (B) physiologically acceptable salts thereof."

In column 10, lines 26 28 should read as follows:

2 .CIHOH) .CH and 'CH .CH(0H).CH .0.CH .CH(0H).CH .O.CH .CH(OH).CH

In Claim 11, the last formula should read -CH .CH (OH) .CH .O.CH .CH (OH) .CH .O.CH .CH (OH) .CH

The formula in column 4, lines 60 to 70 should read:

CH I CH CH I CH CO C C0 CO C CO CH .N ICZ TAT A NA? C.N.CH

l I.C C.I- LC. LI

l l COONa COONa FORM FO-KOSO (IO-69) USCOMM'DC GO37G-Pfl9 U45. GOVEIINMINT PR NTING OFFICI: IQI'I O IGA-JJ4 Patent No 3,692 ,824 The last two lines in Claim 3 should read: Page 2 the group consisting of -CH .CH(OII) .CH and -CH .CH(0H).CH(OI1).CH

The formula in Claim 6 should read:

(2H3 en I CH3 I CH3 co co A c0 co v I i C cn nfix C.N.CH2.CH(0H) .cH(oH).cH .N.c lcl. N.cH 1.c 0.1% I.(: c I

I c COOH coon Signed and sealed this 25th day of September 1973.

(SEAL) Attest:

Q EDWARD M.FLETCHER,JR. RENE D. TEGTME YER Attesting Officer Acting Commissioner of Patents shown en the at1:. a.c h 'ad sheets.

fIA-titest:

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No. 3 92 Dated September 1 1972 A Lars Bjork et'al. I

Inventor(s) It is certified that error afipears in the above-identified patent and that said Letters Patent are hereby corrected as shown below! In vthe grant (only) insert columns 1, 2, :3 and 4, as

, si ed- 1121 seal ed this 15th day-of October 1974.

McCOY M. mason JR. c. MARSHALL DANN Commissioner. of Patents Attesting Officer USCOMM'DC 6037 6-P69 ORM PC3-1050 (10-69) I u.s sovnnuzrn nmu'mo OFFICE: 8 69 93 o NOVEL 3,5-SUBSTITUTED 2,4,6- TRHODOB'ENZOIC ACIDS AND SALTS THEREOF.

. RELATED CASES The present application, which is a continuation-inpart, discloses and claims subject matter common to copending US. Patent application Ser. No. 689,724 filed on Dec. ll, 1967, and now abandoned.

The present invention relates to novel 3,5-substituted 2,4,6-triiodobenzoic acids adapted to be used,

' for example,.for the visualization of body cavities.

More particularly the present invention relates to compounds having the following formula:

wherein R, is a member selected from the group consisting of methyl and ethyl, and R, and R, are each a member selected from the group consisting of acetyl and propionyl, and wherein A is an alkylenegroup substitutedby at least 'one substituent of the formula OH, said alkylene containingfrom three to inclusive carbon atoms and being optionally broken by one or more oxygen bridges of the formula .--O-- V and physiologicallyacceptable salts thereof. According to the bridge l y l :T -f?:,.

has each nitrogen thereof located at a distance of 2 carbon atoms from a group --OH. in this connection, preferably no more than one oxygen atom is bound to one and the same carbon atom in the bridge A. The

a-suitable embodiment of the invention Page 2 OH; I

wherein A is an alkylene group substituted by at least one substituent of the formula OH;said alkylene containing from three to 15 inclusive carbon atoms and being optionally broken by one or more oxygen bridges of the formula '0, or physiologically acceptable salts thereof, e.g.the sodiumsalt, methylglucamine salt or cthanolamine salt.

As an example of such valuable compounds can be mentioned:

- cm I oo o carr r-c I-ii bridge A suitably contains 3 10 carbon atoms in the alkylene group.

Examples of the bridge A in the above formulas are -CH,.CH(OH ).CH, 0t CH .CH(OH).CH,.O.CH,.CH(OH).CH, or --CH .CH(OH).CH,.O.CH .CH,.O.CH .Cl-HOH).CH,

-Cl-I,.CH(OH-).CH,.O.(CH,) .O.CH,.CH(OH).CH, 1

Or I V or physiologically acceptable'salts thereof, e.g. the

sodium salt or methyl glucamine salt or ethanolamine salt.

The new compounds are very useful as X-ray contrast agents; A preparation for carrying out the X-ray investigations may suitably consist of a mixture, such as an aqueous solution, or contain a physiologically acceptable solid carrier, the preparation being preferably in tablet form or in the 'formjof'any other suitable dosage unit; and the mixture containing one or more of the-aforesaid compounds as active contrast-producing substances.

In applying a preparation containing the contrast producing agent according to 'the invention, the preparation is administered to the body of the test object after which the body is exposed to X-rays photographic or direct observation on a fluorescent screen or some otherconventional X-ray technics is carried out in the usual manner. The dosage .of the contrast producing agent is selected in accordance with the category of the case to be investigated so that a suflicient contrast effect is attained.

One example of the various body cavities which can be visualized by the new compounds or by preparations containing the new compounds is the gastro-intestinal tract. in this instance the contrast-producing agent is in solution. it is also possible to visibilize the intestines by introducing the contrast-producing agent rectally in the form of an' enema. Another example is the advantageous visualization of blood vessels after the injection of the contrast-producing agent in the form of a sterile solution. it is of particular value that subsequent to intravenous injection of the contrast-producing agent, the latter is excreted not only with the urine but alsowith the bile and makes possible the visualization of the bile ducts and gall bladder in an advantageous mannenFurtherexamples are'the use of the iodine compounds in hysterosalpingography, cholangiography, urethrography, sialography, arthrography and urography. I

The novel compounds according to the invention have a low toxicity, e.g. when they are given intravenously or orally, and present excellent charac te'ristics as X-ray contrast agents.

As carriers for the novel compounds can be men tioned conventional additive substances, such as water with regard to injection solutions andextenders with regard to tablets.

if the preparation comprising a novel 3,5-substituted 2,4,6-triiodobenzoic acid according to the invention is in the form of an aqueous solution, the concentration of'the active compound is chosen in accordance with the field of use. Preferably a content is chosen which exceeds grams per 100 ml solution. However, generally a much higher content is chosen, e.g. in the order of 20, 30, 40, 50 or 60 grams or more per 100 ml solution.

The new compounds are also useful as intermediates for the synthesis of other X-ray contrast agents. The new compounds are also useful for the preparation of solutions having high density. Such solutions are useful for the separation of cells and cell fragments by centrifugation. I

The aforesaid novel 3,5-substituted 2,4,6- triiodobenzoic acids are produced by reacting compounds of the formula:

As examples of the bifunctional compounds of the 6s type Y.A.X or corresponding epoxide compounds obtainable' from the compounds Y.A.X by splitting off hydrogen halide can be mentioned the following:

- administered to the body perorally either as a solid or or corresponding halogen hydrin's, -and bifunctional. glycerine derivatives of the formula X CH, CH(OH) I CH, Y, e.g. dichlo'roh'ydrin'and dibromohydrin', or corresponding epoxy compounds of the formula which gives the bridge --CH,.-CH(OH).CH(OH).CH,

The reaction is preferably carried out in a solvent, e.g. water or an aqueous liquid, and there is suitably added an alkaline reacting substance, e.g. alkali metal hydroxides, e.g. NaOH, the alkaline reactingsubstance acting as a catalyst. The alkaline substances may also act as an acceptor for hydrogen halide if this substance is released in the reaction.

The reactions are elucidated by the following reaction which is carried out in.

NaOH solution: I II ICH: I CH: CH! I CH1 co co c 6 CH bl-(K r z-r r-n z n-u-c oat-on, 1'0 0 or 1-o I-r hooNa doom cu, r cm o-N-cm aqueous, alkaline, e.g. 

2. A compound as claimed in claim 1, wherein the bridge has each nitrogen atom thereof located at a distance of two carbon atoms from a group -OH and no more than one oxygen atom is bound to one and the same carbon atom in the bridge A.
 3. A compound as claimed in claim 1, wherein the bridge A of the compound is a member selected from the group consisting of -CH2.CH(OH).CH2 1- and -CH2.CH(OH).CH(OH).CH2- . -.
 4. A compound selected from the group consisting of (A) compounds of the formula
 5. A compound of the formula
 6. A compound of the formula
 7. A compound selected from the group consisting of (A) compounds of the formula
 8. A compound as claimed in claim 7, wherein the bridge has each nitrogen atom located at a distance of two carbon atoms from a group -OH and that no more than one oxygen atom is bound to one and the same carbon atom in the bridge A.
 9. A compound as claimed in claim 7, wherein the bridge A is a member selected from the group consisting of -CH2.CH(OH).CH2.O.(CH2)4.O.CH2.CH(OH).CH2- and -CH2.CH(OH).CH2.O.(CH2)2.O.CH2.CH(OH).CH2- and -CH2.CH(OH).CH22.O.CH2.CH(OH).CH2- and -CH2.CH(OH).CH2.O.CH2.CH(OH).CH2.O.CH2.CH(OH).CH2- and and -CH2.CH(OH).CH2.O.CH2.CH2.O.CH2.CH2.O.CH2.CH(OH).CH2- .
 10. A compound selected from the group consisting of (A) compounds of the formula
 11. A compound of the formula
 12. A compound of the formula 